Influence of different HRT regimens on mammographic density

OBJECTIVES: A prospective, randomized, open-label study was conducted to evaluate effects on mammographic density in postmenopausal and late perimenopausal women receiving continuous combined or sequential combined hormone replacement therapy (HRT). METHODS: The subjects were randomized to treatment with low-dose continuous combined HRT containing 1 mg 17beta-estradiol plus 0.5 mg norethisterone acetate (Activelle) or a sequential combined HRT regimen consisting of 0.625 mg conjugated equine estrogens for 28 days plus 5 mg medrogestone for 14 days (Presomen). Mammograms were obtained at baseline and after 9 cycles (each 28 days) of treatment. RESULTS: The majority of women (approximately two-thirds in each treatment group) had no changes in mammographic breast density between baseline and the final study visit. There were no marked differences between treatment groups. Approximately 20% of women in both groups had a slight increase in mammographic density. Only 10-14% of women in both groups had a pronounced increase in mammographic density. The analyses of the degree of change showed no remarkable differences between treatments. CONCLUSION: These results indicate that the increase in mammographic density with a low-dose continuous combined HRT regimen is no greater than that with a sequential combined HRT regimen. The type of progestogen does not have an impact on the extent of mammographic density changes.     

Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women.

OBJECTIVE: To determine the endometrial effects of raloxifene 60 mg/day in postmenopausal women as assessed by vaginal bleeding and endometrial thickness. DESIGN: Data from 1157 postmenopausal women were analyzed from a database consisting of four independent, double-blind, randomized, placebo-controlled trials (range = 6-30 months duration), a 24-month open-label randomized, cyclical hormone replacement therapy (HRT)-controlled trial, and a 6-month double-blind, randomized, unopposed estrogen-controlled trial. Vaginal bleeding rate was derived from self-reported adverse events collected at least every 6 months. Endometrial thickness was measured by ultrasonography at regular intervals. RESULTS: Raloxifene 60 mg/day was not significantly different from placebo with regard to the incidence of vaginal bleeding, the baseline-to-endpoint change in endometrial thickness, or the proportion of women experiencing an increase in endometrial thickness above baseline after either 12 or 24 months of therapy. Unexpected bleeding was reported significantly more frequently in the unopposed estrogen groups compared with the raloxifene group (raloxifene 60 mg/day, 0% versus estrogen, 50%; p = 0.002). A significantly greater baseline-to-endpoint increase in endometrial thickness was observed in both the HRT and estrogen groups compared with their respective raloxifene comparison group (raloxifene 60 mg/day, 0.01 +/- 2.0 mm versus HRT, 1.8 +/- 3.2; p < 0.001; raloxifene 60 mg/day, 1.1 +/- 1.7 mm versus estrogen, 7.8 +/- 3.8; p < 0.001). No cases of endometrial hyperplasia or cancer were diagnosed in the placebo or raloxifene 60 mg/day groups. Endometrial hyperplasia was diagnosed in one case in the HRT group and in two cases in the estrogen group. CONCLUSION: Raloxifene 60 mg/day for up to 30 months is not associated with vaginal bleeding or increased endometrial thickness in postmenopausal women.     

Quantification of ovarian stromal Doppler signals in postmenopausal women receiving hormone replacement therapy

OBJECTIVE: To investigate the effect of continuous-combined hormone replacement therapy (HRT) on ovarian circulation, we used three-dimensional power Doppler ultrasound to assess ovarian stromal blood flow in postmenopausal women. DESIGN: Forty healthy, postmenopausal women were enrolled in this prospective, controlled study. They were divided into two groups: the control group (20 patients with no HRT treatment) and the HRT group [initially 20 patients, but later 15 patients who completed the study, using continuous-combined conjugated equine estrogen (0.625 mg/day) plus medroxyprogesterone (5 mg/day)]. All patients underwent transvaginal three-dimensional power Doppler ultrasonography at the time of recruitment and 3 months later. The ovarian stromal flow indices, including vascularization-flow index (VFI), flow index (FI), and vascularization index (VI), were measured. Blood withdrawals for serum follicle-stimulating hormone and estrogen level testing were obtained before and after 3 months of treatment. RESULTS: All the variables in the hormone profile showed significant difference (P < 0.05) after 3 months of treatment in the HRT group. Of interest, the three-dimensional power Doppler indices of ovarian stromal flow, VFI (0.13 +/- 0.11 --> 0.59 +/- 0.49), FI (30.47 +/- 12.06 --> 38.41 +/- 10.21), and VI (0.31 +/- 0.27 --> 1.12 +/- 0.95) all showed significant increase (P < 0.05) after 3 months of HRT treatment. CONCLUSIONS: There was a significant increase in ovarian stromal flow indices after 3 months of treatment in the HRT group, but not in the controls. Monitoring the ovarian flow changes by three-dimensional power Doppler may be of clinical importance when HRT is given.     

Prevention of postmenopausal bone loss with long-cycle hormone replacement therapy

OBJECTIVE: Postmenopausal bone loss and osteoporotic fractures can be prevented by hormone replacement therapy (HRT). However, opposed HRT may increase the risk of breast cancer above that associated with estrogen alone and in non-hysterectomized women estrogen substitution alone increases the risk of uterine cancer, which triggered renewed interest in long-cycle HRT regimens (estrogen replacement therapy with progesterone-free intervals up to 6 months). The effects on bone of such long-cycle HRT regimens are unknown. The objective of the present study was to compare the effects on bone and the endometrium of long-cycle HRT and conventional HRT. METHODS: Seventy-three healthy non-hysterectomized postmenopausal women were randomized to either conventional HRT (estradiol (E2) 2 mg/d during 12 days, E2 2 mg/d plus 1 mg/d of norethisterone acetate (NETA) during 10 days, E2 1 mg/d for 6 days) or long-cycle HRT treatment (two cycles with E2 2 mg/d during 28 days, followed by one cycle of conventional HRT and repeated every 3 months). Primary endpoint was the change in bone mineral density (BMD) at the lumbar spine (LS) over 24 months. RESULTS: BMD at LS increased significantly versus baseline in both treatment groups (conventional HRT +3.8 +/- 0.6%, long-cycle HRT +3.3 +/- 0.5%, p < 0.0001 for both) with no significant difference between treatment groups over 24 months. Similar significant BMD increases versus baseline were observed at the femoral neck, while biochemical markers of bone turnover (osteocalcin and deoxypyridinoline) were significantly decreased over 24 months. There were no endometrial or breast related adverse events reported. CONCLUSION: Long-cycle HRT may be a valid alternative to conventional HRT with regard to protection against postmenopausal bone loss.     

The role of hormone replacement therapy in endometrial polyp formation

OBJECTIVE: To evaluate the iatrogenic effect of different protocols of hormone replacement therapy (HRT) on endometrial polyp formation adjusting for the confounding effects of other factors such as age, parity, weight and menopausal status at menopause. METHODS: Out of 2685 menopause patients 375 (13.9%) eligible patients were enrolled. Patients were randomized to three HRT types and three equal groups were formed. The first group received Premelle 2.5 mg (Group-I) (0.625 mg conjugated estrogen + 2.5 mg medroxyprogestorone), the second received Kliogest (Group-II) (2 mg estradiol + 1 mg norethisterone) and the last received Livial (Group-III) (2.5 mg tibolone) at least for 36 months without giving a break. After the first 18 months patients had their first office hysteroscopy and it was repeated in every 6 months until the end of third year to find out new and recurrent endometrial polyps. RESULTS: Multiple regression analysis revealed that the type of HRT, late menopause and obesity increased the occurrence of endometrial polyps. In Group-I five polyps, in Group-II ten polyps and in Group-III two polyps were detected. There were significant differences between G-II and G-I and G-II and G-III (P < 0.05), but there was no significant difference between G-I and G-III (P > 0.05). 82.3% of the polyps were detected in the third and fourth hysteroscopic examinations. Endometrial polyp recurrence was encountered in 4 (23.5%) patients, 1 in G-I and 3 in G-II without a significant difference (P > 0.05). No malignancy was detected in any of the specimen. CONCLUSION: We observed that endometrial polyp formation may be dependent on the type and dosage of the estrogen and progestogen. Especially a progestogen with high antiestrogenic activity may play an important preventive role in the development of endometrial polyps.     

The benefits of androgens combined with hormone replacement therapy regarding to patients with postmenopausal sexual symptoms

OBJECTIVE: To evaluate the benefits and risks of hormone replacement therapy (HRT) combined with methyltestosterone (MT) in postmenopausal women with sexual dysfunction. DESIGN: This study was a randomized, double-blind, placebo-controlled and crossover trial. Eighty-five women using HRT were divided into four treatment groups: GI-HRT plus placebo for 4 months; GII-HRT plus MT 2.5mg/day for 4 months; GIII-HRT plus placebo for 2 months and then replaced with HRT plus MT 2.5mg/day for 2 months; GIV-HRT plus MT 2.5mg/day and then replaced with HRT plus placebo for 2 months. Blood was collected at baseline, after 2 months (T1) and 4 months (T2) of treatment for hormone determinations of estradiol, FSH, total and free testosterone, GOT, GPT, glucose, total and fractions of cholesterol and triglycerides. All participants answered clinical questions and a validated questionnaire of modified McCoy's sex scale. RESULTS: The association of HRT with MT 2.5mg/day did not significantly change liver enzymes or increase cardiovascular risk factors. The patients of GII, GIIII and GIV when using MT presented amelioration of sex symptoms, mainly satisfaction and desire (p<0.01); however, GIII at T1 (1.3+/-0.3) presented similar problem score results as compared to GIII at T2 (1.5+/-0.6). CONCLUSION: All data suggest that combined HRT-androgen therapy may be beneficial for postmenopausal women receiving HRT who continue to complain of sexual difficulties or for postmenopausal women with sexual complaints who are not undergoing estrogen therapy.     

Endocrinology: Long-term medical therapy for leiomyomata uteri: a prospective, randomized study of leuprolide acetate depot plus either oestrogen--progestin or progestin 'add-back' for 2 years

Treatment of women with leiomyomata with gonadotrophin releasinghormone agonists (GnRHa) for >6 months is not recommendedbecause of concerns regarding adverse sequelae of prolongedhypoestrogenism. It has been postulated that addition of low-dosesex steroids to GnRHa treatment, i.e. ‘add-back’therapy, may avert some of these adverse effects (acceleratedbone resorption, vasomotor flushes) without altering the efficacyof GnRHa therapy. To evaluate the effects of long-term GnRHatherapy on uterine size, bleeding patterns, bone mass and lipids,51 pre-menopausal women with leiomyomata were treated with theGnRHa leuprolide acetate depot, 3.75 mg every 4 weeks for 2years. After 3 months of leuprolide therapy, the women wererandomized to receive either low-dose continuous oestropipate,0.75 mg daily, plus cyclic norethindrone, 0.7 mg on days 1—14each month (the oestrogen–progestin add-back group) orhigher-dose norethindrone, 10 mg daily (the progestin add-backgroup), for the remaining 21 months. Mean uterine volume decreasedby 40% in both treatment groups during the first 3 months onleuprolide treatment. There was no significant change in uterinesize following oestrogen–progestin add-back. However,mean uterine volume in the progestin add-back group increasedto 87% of pre-treatment size by treatment month 12 and 95% ofpre-treatment size by treatment month 24. Mean bone densityof the lumbar spine as measured by dual X-ray absorptiometrydecreased significantly by 2.6% during the first 3 months inall patients, but did not change significantly following steroidadd-back in both treatment groups during the final 21 treatmentmonths. There were parallel and significant increases in meanhaematocrits (Hct) of 4.8% in the oestrogen—progestingroup and 7.8% in the progestin group over the 2-year treatmentperiod. Mean serum high density lipoprotein (HDL) cholesterolconcentration was unchanged in the oestrogen—progestinadd-back group but decreased by 36% in women receiving progestinadd-back. By 6 months after completion of treatment, mean uterinevolume, leiomyoma-related symptoms, Hct and bleeding patternshad returned to pre-treatment values. Thus, the oestrogen—progestinadd-back regimen was superior or equal to the progestin add-backregimen in all safety and efficacy parameters studied; the latterregimen was associated with regrowth of myomatous uterine volumeand with marked depression of cardio-protective HDL cholesterolconcentrations. One 50 year old woman in the oestrogen—progestingroup developed a leiomyosarcoma which was suspected by sonographicchanges in leiomyoma appearance and was thought to be unrelatedto treatment. In conclusion, GnRHa plus oestrogen—progestinadd-back therapy may provide a long-term (i.e.>6 month) medicaltreatment option in women with leiomyomata.     

Low-dose danazol after combined surgical and medical therapy reduces the incidence of pelvic pain in women with moderate and severe endometriosis.

The most effective therapy for endometriosis is a matter for debate. The aim of the present randomized study was to evaluate the efficacy of low doses of danazol on recurrence of pelvic pain in patients with moderate or severe endometriosis, who had undergone laparoscopic surgery and 6 months of gonadotrophin-releasing hormone analogue (GnRHa) therapy. After surgery, 28 patients with moderate or severe endometriosis underwent therapy for 6 months with GnRHa i. m. every 4 weeks. They were then randomized into two groups: group A (14 subjects) was treated with 100 mg/day danazol for 6 months; group B (14 subjects, control) did not receive any type of therapy. After 12 months of treatment, group A had a significantly (P < 0.01) lower pain score than group B. There was no significant difference between the groups in oestrogen concentrations, bone mineral density or side-effects. The results suggest that low-dose danazol therapy reduces recurrence of pelvic pain in patients with moderate or severe endometriosis, treated surgically, and has few or no metabolic side-effects.     

Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women

BACKGROUND: Recent studies have revealed that HRT may increase the risk for atherosclerotic vascular disease (ASVD). METHODS: We investigated the effects of HRT via different administration routes on the markers for ASVD and endothelial function in healthy postmenopausal women. The oral HRT group (n=18) received conjugated equine estrogen 0.625 mg/day; the transdermal HRT group (n=18) received 17beta-estradiol (E2) gel 0.6 mg/day for 6 months. The control group (n=30) had no treatment for 6 months. RESULTS: The C-reactive protein (CRP) rose from 0.129+/-0.116 to 0.752+/-0.794 mg/dl (P<0.01) in the oral HRT group but remained unchanged in the transdermal HRT and control groups. The flow-mediated vasodilation (FMD) in the brachial artery was increased significantly by HRT from 6.0% before oral HRT to 14.7% after oral HRT (P<0.001) and from 5.9% before transdermal HRT to 13.9% after transdermal HRT (P=0.001). CONCLUSIONS: These data suggest that oral estrogen induces ASVD risk by increasing acute inflammation; however, transdermal estrogen avoids this untoward effect. Additionally, transdermal estrogen exerts a positive effect on endothelial function similar to that of oral estrogen. Therefore, the transdermal route might be favourable in terms of ASVD risks.     

Differential effects of progestogens, by type and regimen, on estrogen-metabolizing enzymes in human breast cancer cells

OBJECTIVES: To investigate the in vitro effects of five progestogens commonly used in hormone replacement therapy (HRT) on estrogen-metabolizing enzymes in human breast cancer cells. METHODS: The human hormone-dependent breast cancer cell lines T47D, MCF-7, and MCF-7aro were cultured with estradiol (E(2)) and progestogens. The mRNA levels of estrogen-metabolizing enzymes were determined by RT-PCR or Northern blot, and enzyme activities by radiolabeled substrates. Cell proliferation was measured by bromodeoxyuridine incorporation. In vitro models for continuous combined regimen (CCR) and sequential combined regimen (SCR) were established to mimic the in vivo conditions of HRT. RESULTS: Medroxyprogesterone acetate (MPA) plus E(2) (10(-8)M) stimulated the mRNA levels and activities of estrogen-activating enzymes aromatase (at 10(-8)M MPA), 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1) (at 10(-6)M), and sulfatase (at 10(-8) to 10(-6)M) compared to E(2) only. Progesterone also stimulated enzyme activity, but to a lower magnitude. Levonorgestrel, norethindrone, and dienogest showed no enzyme stimulation. The estrogen-inactivating enzymes 17beta-hydroxysteroid dehydrogenase type 2 and sulfotransferase were not affected by any of the progestogens tested. However, all the progestogens (at 10(-8) to 10(-6)M) inhibited E(2)-stimulated cell proliferation. While increased aromatase and 17betaHSD1 activities were observed in the CCR model, no significant enzyme stimulation was observed in the SCR model. CONCLUSIONS: The present study suggested that progestogens exert different actions on estrogen-metabolizing enzymes in breast cancer cells dependent on the specific progestogen and regimen used. Further studies are needed to elucidate whether MPA, a progestogen currently used in HRT, leads to a higher risk of breast cancer development than other progestogens.     

Effect of postmenopausal hormone replacement therapy on cardiovascular performance

SUMMARY: Postmenopausal hormone replacement therapy (HRT) has usually been evaluated the relationship with atherosclerotic disease, whereas its effect on direct cardiac functions hasn't been investigated in detail. This study was planned to investigate the long-term effects of HRT on cardiac functions and exercise performance. METHODS: Thirty-six postmenopausal women (mean age: 51 +/- 4 years, 39-60 years) were prospectively analyzed with pulsed wave Doppler echocardiography and symptom-limited exercise stress test before HRT (oral 0.625 mg conjugated estrogen and 2.5 mg medroxyprogesteron acetate/day), and at the third and the sixth months. The effect of HRT on left ventricular ejection fraction (EF), early filling velocity (E wave) and late filling velocity (A wave), E wave deceleration time (EDT), E/A ratio, myocardial performance index (MPI), exercise duration and METS changes were examined. RESULTS: HRT did not significantly alter the left ventricular EF. At the third month of HRT, there was an insignificant increase in E wave, EDT, and E/A ratio, whereas an insignificant decrease was noted in MPI (P > 0.05). However, at the sixth month of HRT, these changes became significant (68 +/- 12 vs. 75 +/- 13 cm/s, P < 0.01; 171 +/- 24 vs. 184 +/- 14 ms, P < 0.01; 1.01 +/- 0.23 vs. 1.11 +/- 0.27, P < 0.01, and 44 +/- 9 vs. 39 +/- 8%, P < 0.001, respectively). On the other hand, exercise duration and exercise METS values showed significant improvements at the third month of HRT (423 +/- 104 vs. 482 +/- 104 s, P < 0.001; 8.2 +/- 1.7 vs. 9.1 +/- 2 METS, P < 0.001). These improvements also continued at the sixth month of HRT. In conclusion, postmenopausal HRT leads to a progressive improvement on left ventricular function parameters, and in parallel, in exercise performance.     

The efficacy of two dosages of a continuous combined hormone replacement regimen

OBJECTIVES: To evaluate the efficacy of a low-dose combination of estradiol (E2) and norethisterone acetate (NETA) on bone markers, lipid and bleeding profiles and menopausal symptoms. METHOD: Ninety-six healthy Chinese postmenopausal women were allocated randomly to receive 1 mg E2/0.5 mg NETA (low-dose hormone replacement therapy (HRT)) or 2 mg E2/1 mg NETA (high-dose HRT) for 6 months. RESULTS: Bone resorption markers (collagen I N-terminal telopeptides (NTX) and deoxypyridinoline (dPyr)) were significantly reduced; -66 and -32%, respectively, in high-dose HRT versus -55 and -24%, respectively, in low-dose HRT. Bone-specific alkaline phosphatase remained unchanged with either combination of hormones. Total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels were decreased significantly (-12 and -13%, respectively, in high-dose HRT vs. -7 and -8% in low-dose HRT). High density lipoprotein cholesterol (HDL-C) was decreased to a lesser extent in low-dose HRT and triglycerides (TG) levels remained unchanged. Both the low and high-dose HRT were effective in alleviating menopausal symptoms. After 6 months of treatment, 2% of women in the low-dose HRT were bleeding compared with 23% in the high-dose HRT. Breast pain occurred in 2% of women in low-dose HRT compared with 15% in high-dose HRT. The endometrium in the majority of the women remained normal. CONCLUSION: Menopausal symptoms were reduced effectively in postmenopausal women on either low-dose or high-dose HRT. TC, LDL-C levels and bone resorption markers were reduced in a dose-dependent manner. Low-dose HRT provided a better bleeding profile and the incidence of breast pain was low.     

Comparison of transdermal estradiol and tibolone for the treatment of oophorectomized women with deep residual endometriosis

Study objective: To compare the effect of HRT with transdermal estradiol and that of treatment with tibolone in post-menopausal women with residual endometriosis. Materials and Methods: 21 women with residual pelvic endometriosis after bilateral oophorectomy with or without hysterectomy were enrolled in the study and were randomized to HRT with transdermal estradiol 50 mg twice weekly (n=10) associated with cyclic medroxyprogesterone acetate 10 mg daily in women who preserved uterus, and to treatment with tibolone 2.5 mg administered orally once a day (n=11). The duration of both treatments was scheduled to last at least 12 months. Residual endometriosis was located in the bowel wall in four patients, in the rectovaginal septum in six and deeply in the retroperitoneal pelvic space in six. All women were symptomatic before oophorectomy. Results: All the women were followed for 12 months. No patient suspended therapy because of side effects. Four patients of the estradiol group experienced moderate pelvic pain during treatment compared with only one patient in the tibolone group. One patient in the estradiol group reported severe dyspareunia. Conclusion: Although our series is very small, it seems that tibolone may be a safe hormonal treatment for post-menopausal women with residual endometriosis.     

Estrogen with interrupted progestin HRT: a review of experimental and clinical studies

This review outlines the basic principles of a novel interrupted progestin HRT regimen in which estrogen is administered continuously, and progestin is given in a 3-days on, 3-days off pulsed fashion. The rationale for this regimen is to prevent receptor down-regulation and allow increased estrogen and progestin sensitivity during the progestin-free periods. Background information is provided including the reasons for poor patient acceptance of HRT, and the concerns of the potential association of HRT with breast and endometrial cancer. Experimental studies in the rat are described which provide evidence in support of the rationale for the interrupted progestin regimen. Clinically, two pilot studies examining symptom control, bleeding rates and safety of the interrupted progestin regimen, as well as preliminary results of a third study examining the usefulness of this regimen for addback therapy in GnRH agonist treated patients, are outlined. The preliminary results of phase III trials are presented. These clinical studies all demonstrated good symptom control, low bleeding rates, endometrial protection, and excellent patient acceptance. The combination of continuous estrogen with interrupted progestin appears to result in increased sensitivity to estrogen and progestin in estrogen responsive tissues. As a result, lower doses of estrogen and progestin may be used for HRT with good biological effects. Further clinical studies, preferably in prospective randomized trials, are required to demonstrate an advantage of this new regimen compared to continuous combined HRT.     

Effect of postmenopausal hormone replacement on atherosclerosis in femoral arteries.

OBJECTIVES: On the basis of epidemiological and experimental data, it has been supposed that hormone replacement therapy (HRT) inhibits atherosclerosis in postmenopausal women. This randomized controlled trial examined whether 1 mg 17beta-estradiol daily, combined cyclically with 0.025 mg gestodene in every month (HRT 1), or in every third month (HRT 2) slows the increase of intima-media thickness in femoral arteries compared with no HRT. METHODS: Healthy postmenopausal women (n=321) with an increased risk for future vascular disease as indicated by >1 mm of intima-media thickness in the carotid arteries were equally randomized to one of the three groups for 48 weeks. Ultrasound scans of femoral arteries were recorded at study start and study end, together with a thorough clinical examination and laboratory work-up. RESULTS: Complete scans were obtained in 260 of the 264 subjects who participated until study end. Mean maximum intima-media thickness of four femoral artery segments (common and superficial, both sides) was 0.93+/-0.37 mm (mean+/-S.D.) at study start. It increased by 0.02+/-0.05, 0.02+/-0.05, and 0.03+/-0.05 mm in the HRT 1, HRT 2 and no HRT groups, respectively (HRT 1 versus no HRT, HRT 2 versus no HRT; both P>0.2). Compared with no HRT, HRT significantly lowered follicle stimulating hormone, low-density lipoprotein cholesterol, and fibrinogen. CONCLUSIONS: In this 1-year trial, irrespective of the progestogen dose used, HRT with 1 mg 17 beta-estradiol did not inhibit progression of femoral artery atheroslerosis in postmenopausal women with subclinical vascular disease.     

Hormonal replacement regimens and bleeding

Hormone replacement therapy may increase the quality of life of postmenopausal women. Any regimen need to offer long-term endometrial safety. It is a standard to consider the co-administration of a sequential progestogen when estrogen replacement should be initiated in non-hysterectomized women. It is almost impossible to decide which combination of an estrogen and a progestogen seems to be optimal as individual tolerance of HRT may very well limit acceptability despite metabolic benefits and proven endometrial safety of a given combination. Several combinations of oral and transdermal estradiol or conjugated equine estrogens, oral progestogens, transdermal norethisterone acetate and levonorgestrel, and intrauterine levonorgestrel may achieve endometrial safety. It is noteworthy that there is no uniform correlation between the timing of onset of bleeding induced by any sequential estrogen and progestogen replacement and a certain pattern of histology. Therefore, although it is likely, there is no absolute reassurance that regular bleeding on or after day 11 of progestogen administration rules out abnormal histopathology. Transvaginal sonography seems not to be of pivotal importance to screen asymptomatic women on replacement therapy for detection of serious abnormal endometrial findings such as hyperplasia and endometrial cancer. Continuous combined hormone replacement therapy or the use of tibolone may be an alternative in postmenopausal women, who do not want any uterine bleedings after menopause. However, spottings or bleedings most often occur at the beginning of treatment. Vaginal administration of estriol and estradiol for urogenital symptoms of estrogen deficiency may stimulate the endometrium unintentionally. Available data suggest that use of oral estriol may be associated with endometrial hyperplasia and endometrial carcinoma relatively more often compared to sequential HRT. Raloxifene, a benzothiophene derivative acting as a selective estrogen receptor modulator approved for prevention of vertebral osteoporosis, rarely causes uterine bleeding. There is no ideal therapy available to suit women looking for a permanently bleed-free hormonal replacement therapy today.     

Age-related cognitive decline in the menopause: effects of hormone replacement therapy on cognitive event-related potentials

OBJECTIVE: Although epidemiological and clinical studies suggest that hormone replacement therapy (HRT) may protect against cognitive disorders and neurodegenerative diseases, the relation between estrogen and cognition in postmenopausal women remains controversial. METHODS: In a double-blind placebo-controlled, parallel group design study the effects of HRT with the estrogen-progestogen combination Presomen 1.25 compositum((R)) (1.25mg equine conjugated estrogens administered for 21 days plus the progestogen 5mg medrogeston given for 11 days) on event-related potentials (ERPs) in postmenopausal patients with age-related cognitive decline (DSM-IV code 780.9, ICD-10 code R 41.8) were investigated. After a pre-drug comparison with age-matched normal postmenopausal controls, 48 psychotropic drug-free patients aged 60 +/- 6 years were randomized to receive either placebo or verum for 4 months. ERPs were recorded before as well as on the 91-92 days of the study, which thus fell into the estrogen phase of the treatment during the fourth cycle. RESULTS: At baseline, patients showed a lengthening of P300 latency and an attenuation of P300 amplitudes as compared with normal controls. After HRT with Presomen, a significant shortening of P300 latency as compared with placebo was observed. CONCLUSIONS: The baseline P300 differences suggest that in the patient group the aging process was advanced, while after HRT with Presomen a significant improvement and normalization of information processing as indexed by P300 was observed.     

Efficacy and tolerability of fully transdermal hormone replacement in sequential or continuous therapy at two doses of progestogen in postmenopausal women

OBJECTIVES: Two randomized open-label studies were performed to evaluate fully transdermal hormone replacement therapy (HRT) with oestradiol (E2) and norethisterone acetate (NETA) in postmenopausal women. METHODS: Both hormones were delivered by transdermal matrix patches changed twice weekly. Subjects received E2, 50 microg/day and NETA, 170 microg/day or 350 microg/day, either continuously or sequentially. A one-year study (13 cycles of 28 days), including a reference regimen of transdermal E2 and sequential oral progestogen, was followed by a continuation study for a further year in 367 women. RESULTS: All regimens were highly and equally effective in the prevention of hot flushes. The fully transdermal regimens were associated with beneficial changes in the lipid profile. The sequential regimens provided effective scheduling of bleeding around the end of the progestogen phase. The continuous regimens were associated with irregular bleeding, which was rarely severe, and a gradually increasing incidence of amenorrhoea. With sequential or continuous therapy, bleeding was less severe at the lower dose of progestogen than at the higher dose. No endometrial hyperplasia was detected by biopsy in any treatment group. One serous endometrial carcinoma and one endometrial adenocarcinoma were detected. An endometrial thickness >5 mm did not predict the presence of hyperplasia at biopsy. Hormone-related adverse events were typical of those expected for HRT and dermal tolerability of the patches was good. CONCLUSIONS: Fully transdermal sequential or continuous HRT is effective and well tolerated in postmenopausal women. The lower dose of NETA may be preferable, because it confers adequate endometrial protection at a lower dose of progestogen.     

Does postmenopausal hormone replacement therapy affect cardiac autonomic regulation in osteoporotic women?

OBJECTIVE: Postmenopausal hormone replacement therapy (HRT) has been associated with reduced risk of cardiovascular disease; however, the mechanisms remain obscure, and it is not known whether this applies to regimens containing both estrogen and progestin. One possibility is that estrogen would act via enhancement of cardiac autonomic regulation. DESIGN: In this prospective, controlled study of 6-months duration, 22 osteoporotic, postmenopausal women in the intervention group were treated with combined estradiol hemihydrate corresponding to estradiol 2 mg and norethisterone acetate 1 mg with or without clodronate (HRT group). Nine women in the control group received clodronate only. Indices of heart rate variability (HRV) by power spectral analyses and baroreceptor sensitivity (BRS) by phenylephrine test were measured before and after 3 and 6 months of treatment. RESULTS: The total power of HRV remained identical within the groups, although it was higher at 3 and 6-month measurements in the control group than the HRT group. This was mainly due to lower very low frequency and high frequency power in the HRT group. However, no changes in the low frequency/high frequency-ratio of HRV, an index of sympathovagal balance, were observed between and within the groups. Further, during the intervention, no significant changes in BRS (baseline and 6 months: 5.0 +/- 2.1 and 5.1 +/- 2.5 ms/mmHg) within the HRT group was observed. CONCLUSIONS: The impact of estrogen and progesterone on cardiac autonomic regulation seems to be quite modest. Therefore, cardiac morbidity and mortality are probably not mediated by their effects on cardiac autonomic regulation. However, the effects of estrogen alone or more selective estrogen receptor modulators need yet to be clarified in future studies.     

Escitalopram versus ethinyl estradiol and norethindrone acetate for symptomatic peri- and postmenopausal women: impact on depression, vasomotor symptoms, sleep, and quality of life

OBJECTIVE: To examine the efficacy and tolerability of escitalopram (ESCIT) compared to estrogen and progestogen therapy (EPT) for the treatment of symptomatic peri- and postmenopausal women. DESIGN: Forty women (aged 40-60 years) with depressive disorders and menopause-related symptoms were randomly assigned to an 8-week open trial with ESCIT (flexible dose, 10-20 mg/day; fixed dose, 10 mg/day for the first 4 weeks) or estrogen plus progestogen therapy (ethinyl estradiol 5 microg/day plus norethindrone acetate 1 mg/day). Primary outcome measures included Montgomery-Asberg Depression Rating Scale and the Greene Climacteric Scale at week 8. Secondary outcome measures included the Clinical Global Impressions as well as sleep and quality of life assessments. RESULTS: Thirty-two women (16 on EPT, 16 on ESCIT) were included in the analyses. Full remission of depression (score of <10 on the Montgomery-Asberg Depression Rating Scale) was observed in 75% (12/16) of subjects treated with ESCIT, compared to 25% (4/16) treated with EPT (P = 0.01, Fisher's exact tests). Remission of menopause-related symptoms (>50% decrease in Greene Climacteric Scale scores) was noted in 56% (9/16) of women treated with ESCIT compared to 31.2% (5/16) on EPT (P = 0.03, Pearson's chi2 tests). Improvement in sleep, hot flashes, and quality of life was observed with both treatments. CONCLUSIONS: ESCIT is more efficacious than EPT for the treatment of depression and has a positive impact on other menopause-related symptoms. ESCIT may constitute a treatment option for symptomatic menopausal women who are unable or unwilling to use hormone therapy.